LU87414A1 - ADENOSINE DERIVATIVES - Google Patents

Description

_ "R d m.

Derived from 11 adenos ine

The present invention relates to new adenosine derivatives, processes for the preparation of these compounds, the pharmaceutical compositions containing them and their use in medicine. More particularly, the invention relates to substances which act as lipolysis inhibitors.

GB-A-1143150 describes compounds of formula 10

yv-x-B

V

!

AT

N · -N

! there it 15 · · · / w / \ /

Y N N

h ° h2cn Λ | • ·

I I

• - · 20 = Ξ

OH OH

in which Y represents a hydrogen atom or a hydroxyl radical, R represents a hydrogen atom or an alkyl radical, A represents an aliphatic, cyclic or straight or branched, saturated or unsaturated hydrocarbon radical, which may be substituted by one or more hydroxyl and / or acyloxy groups, X is a valence bond or an oxygen or sulfur atom, or an imino radical optionally alkylated or acylated and B represents a hydrogen atom or a naphthyl or phenyl radical possibly substituted.

These compounds are said to exert activity on the heart and circulation.

φ m.

¥ 2

No compound is cited as an example in which -AXB represents a cycloalkyl or cycloalkenyl ring substituted by a hydroxyl radical, nor is it suggested in GB-A-1143150 that any of the 5 compounds described therein would exert antilipolytic activity. We have now discovered a new group of N (6) -monosubstituted adenosine derivatives which differ in structure from those previously described and which act as lipolysis inhibitors.

Consequently, the subject of the present invention is compounds of formula (I):

RNH

15 I

AT

N · -N

I n il / vV (I)

A / M

20 HO \ J

I I

• _ ·

OH OH

in which X represents a hydrogen atom or a chlorine atom, or the methyl radical and R represents a cycloalkyl or cycloalkenyl ring, containing from 5 to 8 carbon atoms, which nucleus is substituted by a hydroxyl radical and is optionally substituted with a C 1 -C 6 alkyl radical, as well as the salts and solvates of these compounds, more particularly the solvates and physiologically acceptable salts of these substances.

It should be understood that when the radical R contains one or more asymmetric carbon atoms, the scope of the invention also extends to all the resulting * * 3 diastereoisomers as well as to their mixtures.

As used herein, the term "cycloalkenyl" refers to a 5 to 8 5 membered ring containing a single double bond. By way of particular examples of the radical R, there may be mentioned the following:

HO

ηη \ HO HO Me î — î / - \ V_ Λ / “λ / - ° H ί î i 1 î i • · - · / \ // / \ / / \ / \ • · · 0Η 15 / \ / \ / \ \ / \ / and \ / • - · · · · · \ / / \ OH HO HO Me 20

Physiologically acceptable and suitable salts of the compounds of general formula (I) include acid addition salts derived from inorganic or organic acids, such as sulfates, phosphates, benzoates, camphosulfonates, p-toluenesulfonates, methanesulfonates , sulfamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarbalyllates. The solvates can be, for example, hydrates.

A preferred class of compounds of formula (I) is that formed by substances in which X represents a hydrogen atom or the methyl radical, more preferably still, a hydrogen atom. Another preferred class of compounds of formula (I) is that formed by substances in which the group R represents a cycloalkyl or cycloalkenyl ring, containing 5 or 6 carbon atoms, substituted by a hydroxyl radical in any position available. The nucleus may optionally be substituted by a C 1 -C 4 alkyl group (for example methyl or ethyl). Even more advantageously, R represents a cycloalkyl nucleus, containing 5 or 6 carbon atoms, substituted by a hydroxyl radical in any available position and optionally substituted by a C 1 -C 4 alkyl radical (for example methyl) on the same carbon atom as the hydroxyl radical.

A particularly advantageous class of compounds of formula (I) is that formed by the substances in which R represents the 2-hydroxycyclopentyl, 4-hydroxycyclohexyl, 3-hydroxycy-clohexyl or 2-hydroxy-2-methylcyclopentyl radical.

The preferred compounds according to the present invention are: N- / 1S, trans) -2-hydroxycyclopenty 1.7adenosine; N - / (IR, trans) -2-hydroxycyclopentyl7adenosine; and their mixtures; • 25 N- (trans-4-hydroxycyclohexyl) -2-methyladenosine; N- (cis-4-hydroxycyclohexyl) adenosine; N- (cis-2-hydroxycyclopentyl) adenosine; N- (trans-3-hydroxycyclohexyl) adenosine; N- (2-hydroxy-2-methylcyclopentyl) adenosine; N- (cis-2-hydroxycyclohexyl) adenosine; as well as their physiologically acceptable solvates and salts.

As compounds in accordance with the invention which are very particularly advantageous, the following may be cited: 5 N- £ "(1S, trans) -2-hydroxycyclopentyl7adenosine and N- £ (1R, trans) -2-hydroxycyclopentyi7adenosine and their mixtures, more particularly N- / 1S, trans) -2-hydroxycyclopentyl, 7adenosine and its physiologically acceptable solvates and salts.

Animal tests have shown that the compounds according to the present invention are inhibitors of lipolysis, that is to say that they decrease the concentrations of free fatty acids in plasma. Therefore, the compounds can be used for the treatment of hyperlipidemias. In addition, as a result of their antilipolytic activity, the compounds have the ability to lower elevated levels of ketones and glucose in the blood and therefore may be of interest in the treatment of diabetes. Since antilipolytic agents have hypolipidemic and hypofibrinogenemic activity, the compounds may also exhibit anti-atherosclerotic activity.

The antilipolytic activity of the compounds according to the present invention has been demonstrated by their ability to lower the concentration of non-esterified fatty acids (NEFAs) in rats which have been fasted and administered by the route oral.

A particularly important group of compounds due to their marked antilipolytic effect is that formed by the substances of formula (I) in which X represents a hydrogen atom and R represents a cyclopentyl ring substituted by a hydroxyl radical and optionally also substituted by a C 1 -C 6 alkyl radical (for example methyl).

In addition to their antilipolytic effect, the compounds of the present invention can independently affect cardiac function by reducing conduction and heart rate. Therefore, the compounds can be used for the therapeutic treatment of a number of cardiovascular disorders, for example cardiac arrhythmias, particularly after. myocardial infarction and angina pectoris. The compounds can also inhibit the release of renin and are therefore of interest for the therapeutic treatment of hypertension and heart failure. The compounds can also be of interest as CNS agents (for example as hypnotics, sedatives, analgesics and / or anticonvulsants).

The present invention therefore relates to a compound of formula (I) or a solvate or physiologically acceptable salt of such a compound for use in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing the concentration of free fatty acids in the plasma and / or reducing conduction and heart rate.

According to another of its characteristics, the present invention relates to a method of treating a human or animal subject suffering from a state in which it is advantageous to decrease the concentration of free fatty acids in the plasma and / or reducing conduction and heart rate, characterized in that an effective amount of a compound of formula (I) or a physiologically acceptable solvate or salt thereof is administered to the subject concerned.

It should be understood that when referring to treatment, it includes both prophylaxis and relief of established symptoms.

Next another of. its characteristics, the present invention also relates to a pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) or a solvate or a physiologically acceptable salt thereof. ci, in combination with a pharmaceutical vehicle and / or excipient to be used in human or veterinary medicine.

The compositions according to the present invention may be presented for administration by the oral, buccal, parenteral or rectal route, or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules suitable for oral administration may contain conventional excipients, such as binding agents, for example a starch or polyvinylpyrrolidone mucilage; fillers, for example lactose, microcrystalline wax and corn starch; lubricants, for example magnesium stearate or stearic acid; disintegrating agents, for example potato starch, croscarmellose sodium or sodium glycolate starch; or wetting agents, such as sodium lauryl sulfate. The compounds can be coated according to methods well known to those skilled in the art. Liquid preparations for oral administration may take the form, for example, of aqueous or oily elixirs, syrups, emulsions, solutions or suspensions, or they may be presented as a dry product to be mixed with water or any other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol syrup, methylcellulose, or carboxymethylcellulose; emulsifiers, for example sorbitan mono-oleate; Non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example methyl- or propyl-p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavoring, coloring and sweetening agents (eg mannitol), as it turns out to be convenient.

For oral administration, the compounds may take the form of tablets or dragees or lozenges suitably shaped.

The compounds of formula (I) may be presented in a form suitable for parenteral administration by injection of bowls, or by continuous infusion and may be presented as unit doses in ampoules or in containers therefor. contain multiple doses with, in this case, additional preservative. The compositions may adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain composing agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder to be mixed with a suitable vehicle, for example sterile pyrogen-free water before use.

The compounds of formula (I) can also be presented in the form of suppositories, containing, for example bases for conventional suppositories, such as cocoa butter and other glycerides.

A suitable dose of the compounds according to the invention for administration to humans (of a body weight of approximately 70 kg) varies from 2 mg to 2 g, preferably from 10 mg to 1 g, from 1 active ingredient, per unit dose which could be administered, for example, 1-4 times per day. It should be understood 9 that the dose may need to be changed on a routine basis, depending on the age and condition of the patient. The dose also depends on the method of administration.

According to yet another of its characteristics, the present invention also relates to the use of a compound of formula (I) or of a solvate or physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition in which it is advantageous to decrease the concentration of free fatty acids in the plasma and / or to reduce the conduction and the heart rate.

The compounds of formula (I) and their physiologically acceptable solvates and salts can be prepared by the methods described hereinafter, which methods constitute another characteristic of the invention. In the following description, groups X and R are as defined with respect to the compounds of formula (I), unless otherwise specified.

According to a first general process (A), a compound of formula (I) can be prepared, by reacting a compound of formula (II): 25 ^

AT

î ri / VV ““ Λ / Ί

I I

OH OH

.r Ά 10 in which L represents a labile group, such as a halogen atom (for example a chlorine atom) or a trimethylsilyloxy radical, or a protected derivative of such a group, on a compound of the formula RNH2, or a salt or a protected derivative of this compound, under basic conditions, reaction followed, when necessary, by the removal of all protective radicals, as described, for example, in process (D). The compounds of formulas (II) and RNH2 can be protected, for example as described below. Thus, a compound of formula (II) can be protected, for example, in the form of the isopropylidene, tribenzoilic or triacetyl derivative and a compound of the formula RNH2 can be protected, for example in the form of the N-benzyl derivative.

The reaction can conveniently be carried out in the absence or in the presence of a solvent, such as an alcohol (for example a lower alkanol, such as propan-2-ol or t-butanol), an ether (for example tetrahydrofuran-20 or dioxane), a substituted amide (for example dimethylformamide), a halogenated hydrocarbon (for example chloroform) or acetonitrile, preferably at an elevated temperature (for example up to reflux temperature solvent), in the presence of a suitable acid scavenger, for example inorganic bases, such as sodium or potassium carbonate, or organic bases, such as triethylamine, diisopropylethylamine or pyridine, or oxides of alkylene, such as ethylene oxide or propylene oxide.

The compounds of formulas (II) and RNH2 and their protected derivatives are known compounds or they can be prepared by conventional methods, for example as described below.

According to another general process (B), a compound of formula (I) in which X represents a hydrogen atom or the methyl radical can be prepared, by transposition of a compound of formula (III): 5

NH

II

R · \ / \

N · -N

I II II

• · · (III) / \\ / \ / aNoi «/ V Ί

I_I

OH OH

In which X represents a hydrogen atom or the methyl radical, or of a protected derivative of this compound, by heating in the presence of a base, such as an alkali metal hydroxide (for example sodium hydroxide) , or an alkali metal carbonate (for example sodium carbonate) and, conveniently, in a solvent, such as an aqueous alcohol (for example ethanol), this transposition being followed, if necessary, by elimination any protective groups. The reaction can advantageously be carried out at a temperature which fluctuates from 50 to 100 ° C.

Compounds of formula (III) and their protected derivatives can be prepared by the reaction of a compound of formula (IV): 12 nh2 N.-N (IV) I II II • · · yw / \ / XNNA 0 'Λ /'

OH OH

in which X represents a hydrogen atom or the methyl radical, or a protected derivative of this compound, on a strong base, such as a Grignard reagent (for example isopropylmagnesium chloride), this reaction being followed by the reaction on an alkylating agent capable of introducing the desired radical R, such as a suitable epoxide or halohydrin. Thus, for example, when R represents the 2-hydroxycyclopentyl radical, this compound can be cyclopentene oxide.

The compounds of formula (IV) and their protected derivatives are known compounds, or they can be prepared by using conventional methods.

According to another general method (C), a compound of formula (I) can be prepared from another compound of formula (I) using conventional methods.

Thus, for example, hydrogenation can be used to prepare a compound of formula (I) in which R represents a substituted cycloalkyl radical, starting from the corresponding compound of formula (I) in which R represents a radical substituted cycloalkenyl. Hydrogenation can also be used to prepare a compound of formula t 13 (I) in which X represents a hydrogen atom, starting from the corresponding compound of formula (I) in which X represents a chlorine atom . In the latter case, the hydrogenation is carried out in the presence of an acid scavenger, such as sodium acetate.

The hydrogenation in accordance with the general process (C) can be carried out using conventional methods, for example using hydrogen in the presence of a noble metal catalyst (for example palladium, Raney nickel, platinum or rhodium). The catalyst can be present on a support, for example, charcoal or alumina, or alternatively, a homogeneous catalyst can be used, such as tris (triphenylphosphine) rhodium chloride. The hydrogenation is generally carried out in a solvent, such as an alcohol (for example methanol or ethanol), an ether (for example tetrahydrofuran or dioxane), an ester (for example ethyl acetate) or water, or in a mixture of solvents (for example a mixture of two or more of two of the compounds which have just been described) at a temperature which varies from -20 to + 100 ° C. and under a pressure of 1 to 10 atmospheres.

It should be understood that in the above-mentioned transformations, it may be necessary or desirable to protect any sensitive radicals in the compound in question to avoid undesirable side reactions. For example, it may be necessary to protect the hydroxyl radicals in a compound of the formula (II), (III) or (IV), or the nitrogen atom in the compound of the formula RNH2 ·

Examples of radicals which protect suitable hydroxyl function include acyl groups (for example hydrocarbylcarbonyl radicals, such as acetyl, benzoyl, pivaloyl and octanoyl); alkyl 35. (for example methyl, t-butyl and methoxymethyl); * 14 aralkyl (for example benzyl, diphenylmethyl, triphenylmethyl and p-methoxyphenyldiphenylmethyl); and silyl (for example trialkylsilyl, such as t-butyldimethylsilyl). Furthermore, neighboring hydroxyl radicals can be protected by an alkylidene radical (for example isopropylidene, or by a disiloxanyl group (for example 1,1,3,3-tetraisopropyldisilox-1,3-diyl). Particularly convenient of the compounds of formulas (II), (III) and (IV) are the isopropylidenic, triacetylic, tribenzoyl and tri-t-butyldimethyl-silyl derivatives.

Examples of suitable N-protecting radicals for a compound of the formula RNt ^ include arylmethyl (eg benzyl) radicals; acyl (for example acetyl) and silyl (for example trimethylsilyl).

Therefore, according to another general method (D), a compound of formula (I) can be prepared by the removal of any protective radicals from a protected derivative of the compound of formula (I) .

Deprotection can be carried out using conventional techniques, such as those described in the book "Protective Groups in Organic Synthesis" by 25 T.W. Greene (John Wiley and Sons, 1981).

Thus, for example, it is possible to remove the acyl radicals protecting the OH function by using methanol, in the presence of a base, such as potassium carbonate, t-butylamine or ammonia. An isopropylidene group can be removed by acid catalyzed hydrolysis (eg, using trifluoroacetic or sulfuric acid). The t-butyldimethylsilyl radicals can be removed by alkaline hydrolysis (for example by using sodium hydroxide in ethanol).

15

An N-benzyl radical can be separated by hydrogenolysis in the presence of a catalyst (for example palladium on charcoal), for example, as described in process (C). An N-acyl radical (for example an acetyl radical) or a trimethylsilyl radical can be removed under acidic or basic conditions (for example by using sodium hydroxide or dilute hydrochloric acid). Separate diastereoisomers of a compound of formula 10 (I) can be obtained by carrying out conventional methods, for example, by synthesis from an asymmetric starting material using any of the methods described in the present specification, or alternatively, where appropriate, by separation of a mixture of isomers of a compound of formula (I) by use of conventional means, for example by chromatography or fractional crystallization.

In the general methods described above, the compound of formula (I) can be obtained in the form of a salt, conveniently in the form of a physiologically acceptable salt. When desired, such salts can be converted to corresponding free bases using conventional methods.

Physiologically acceptable salts of the compounds of formula (I) can be prepared by reacting a compound of formula (I) with a suitable base or acid in the presence of a suitable solvent, such as acetonitrile, acetone , chloroform, ethyl acetate or an alcohol (e.g. methanol, ethanol or isopropanol).

Physiologically acceptable salts can also be prepared from other salts, including other physiologically acceptable salts of the compounds of formula (I), using conventional methods.

The invention will now be further illustrated by the intermediaries and the examples which follow. The temperatures are indicated in degrees Celsius. The organic extracts were dried, where indicated, over anhydrous sodium sulfate. Thin layer (c.c.m.) chormatography was performed on silica. Column chromatography was performed on silica (Merck 7734) unless otherwise indicated and the silica on which reaction mixtures were adsorbed was also silica Merck 7734 unless otherwise specified. Instant column chromatography (CIC) was performed on silica (Merck 9385). The Florisil had a mesh size of 60-100 (it came from BDH). We used

15 the following abbreviations: system A

dichloromethane: ethanol. "0.88 ammonia solution; system B - ethyl acetate: methanol; DEA - N, N-diisopropylethylamine; THF - tetrahydrofuran. The spectra of R.M.N.- H at 250 MHz were obtained on solutions diluted in dimethyl sulfoxide.

Intermediate 1

3-aza-2-oxabicyl acid £ 2.2. l7beptane-3-carboxylic, ester (phenylmethyl)

Azodicarbonamide (5.0 g) was stirred with a solution of potassium hydroxide (7.0 g) in water (12 ml) at 4 °. After stirring in an ice bath for one hour, the mixture was diluted with ice / water (30 ml) and the solution was filtered. The filtrate was diluted with cold ethanol (2 °) (100 ml) and the solid thus obtained was filtered off, washed with ethanol, inethanol and ether so to obtain potassium azodicarboxylate (6.9 g). This compound was mixed with the 17 11 (3-aza-2-oxabicyclo £ 2.2.l7hept-5-ene-3-carboxylic acid (0.82 g) ester (phenylmethyl) (0.82 g) in dry pyridine (60 ml ) and acetic acid (2.02 g) was added with stirring at room temperature. After one hour, an additional fraction of glacial acetic acid (2.0 g) was added and the reaction mixture was stirred for 15.5 hours. The mixture was evaporated to dryness under reduced pressure. Additional acetic acid was added to remove the residual yellow color of the diimide precursor. The residue was partitioned between 0.5M citric acid (75 ml) and ethyl acetate (75 ml) and the organic phase was separated, dried and concentrated under empty. The residue was purified by CIC by eluting with a mixture of ethyl acetate and cyclohexane (1: 2) to obtain the title compound (0.69 g) as an oil, ccm (cyclohexane: ethyl acetate, 2: 1) Rf = 0.25.

Intermediate 2 20 N- (cis-3-hydroxycyclopentyl) carbamic acid, (phenylmethyl) ester

A solution of (phenylmethyl) ester of 3-aza-2-oxabicylo / '2.2.2l7heptane-3-carboxylic acid (0.5 g) in glacial acetic acid (0.5 g) was added. ml) to a stirred suspension of zinc powder (0.35 g) in a mixture of acetic acid and water (1: 1; 4 ml) and the mixture was stirred at 60 ° for 7.5 hours. Additional zinc powder (0.14 g) and acetic acid (1 ml) were added and stirring continued for an additional 16.5 hours. After cooling to room temperature, the reaction mixture was filtered and the excess zinc was removed by washing with 2M hydrochloric acid (20 ί 18 ml). The combined filtrate and washing liquors were neutralized with 8% sodium carbonate and then extracted with ethyl acetate (3x3 ml). The combined organic extracts were washed with brine (30 ml), dried and concentrated. Purification by CIC by eluting with a mixture of ethyl acetate and cyclohexane (1: 1) gave an oil (120 mg) which solidified on standing and which was recrystallized from 10 cyclohexane so as to obtain the compound indicated in the title (70 mg), mp 62-63 °.

Intermediate 3

Trans-N- £ 3- (formyloxy) cyclopenty17 carbamic acid, (phenylmethyl) ester Diethyl azodicarboxylate (1.78 g) was added dropwise to a stirred solution of l (phenylmethyl) ester. N- (cis-3-hydroxycylopen-tyl) carbamic acid (1.19 g), triphenylphosphine (2.68 g) and formic acid (0.47 g) in THF (65 ml), under 20 nitrogen atmosphere and at room temperature. The solution thus obtained was stirred for 2 hours and concentrated to collect a residue which was stirred in ether (20 ml) at about -10 °, under a nitrogen atmosphere, for one hour. The mixture was diluted with cyclohexane (20 ml) and the solid was filtered off and washed with a mixture of ether and cyclohexane (1: 1; about 3 x 20 ml). The combined filtrate and washing liquors were concentrated and the residue thus obtained was purified by CIC by eluting with a mixture of ethyl acetate and cyclohexane (2: 3), so as to obtain the compound indicated in the title (1.18 g), mp 45-48 °.

19

Intermediate 4

Trans-3-aminocyclopentanol hydrochloride

A solution of the trans (N- / 3-5) acid (formyloxyJcyclopentylcarbamic acid (1.1 g) in ethanol (40 ml) was stirred with potassium carbonate (0.25 g) ) at room temperature for one hour. The mixture was then filtered and concentrated in vacuo. The semi-solid thus obtained was dissolved in ethyl acetate (50 ml), filtered the solution and the filtrate was concentrated in vacuo so as to leave a solid which was hydrogenated in ethanol (50 ml) with 5% palladium on carbon (200 mg), serving as catalyst , at atmospheric pressure and for 20 hours The catalyst was then replaced by fresh 5% palladium on carbon (200 mg) and the hydrogenation was continued for a further 20 hours, the reaction mixture was filtered and concentrated the filtrate in vacuo The residue was purified by CIC by eluting with system A (40: 10: 1), so as to obtain an oil (0.26 g) which was diluted with ethanol (40 ml), acidified with 3M ethanolic hydrochloric acid and concentrated in vacuo to collect the title compound (0.34 g).

c.c.m. (system A, 40: 10: 1) Rf = 0.1.

Intermediate 5 £ lo, 2a, 6 ß7-2-Meth hyl-6- [[phenylmethyl) aminq7 cyclohexanol

A mixture of 2-methyl-7-30 oxabicylo / 3.1.OJheptane (5.0 g), benzylamine (5.15 g) and water (0.8 ml) was heated under reflux for 7.5 hours , under a nitrogen atmosphere. Purification by CIC by eluting with the B 540 system: 1) gave the title compound (3.9 g) as a solid, c.c.m. (system B, 20: 1) Rf 0.33.

Intermediate 6 5 [la, 2a, 6H7-6-amino-2-methylcyclohexanol hydrochloride

A solution of / "la, 2a, 6 (37-2-methyl-6-ZT (Phenylmethyl) amino cyclohexanol (3.5 g) in absolute ethanol (75 ml) was hydrogenated on 10% palladium on charcoal (50% aqueous paste; 1.3 g) in absolute ethanol (25 ml) The mixture was filtered and evaporated to a volume of about 100 ml. acidified the solution with approximately 1M ethanolic hydrochloric acid and the solvent was evaporated in vacuo so as to collect a solid which was recrystallized twice from a mixture of isopropanoil and ethyl acetate so as to obtain the compound indicated in the title, PF <5ç'-195 °.

Example 1 N- £ (1S, trans) -2-Hydroxycyclopenty17adenosine A mixture of 6-chloropurine-3-D-riboside (2.87 g) and (1S, trans) -2-aminocyclopentanol hydrochloride was heated ( 1.38 g) at reflux, in. isopropanol (100 ml) containing DEA (3.87 g) for 18 hours. Silica gel (20 g) was added to the cooled solution and the suspension was evaporated under reduced pressure. The dried support was introduced into a column of silica gel (250 g) and elution was carried out with system B (9: 1). Appropriate eluates were collected and evaporated under reduced pressure to obtain a white powder. Crystallization from ethyl acetate and ί 21 methanol gave the title compound as a white powder (2.3 g), mp 163-164 °. c.c.m. (system B, 9: 1) Rf 0.23.

Example 2 5 N- / T (1R, trans) -2-Hydroxycyclopentyl7adenosine

A mixture of 6-chloropurine-3-D-ribosine (2.87 g) and (IR, trans) -2-aminocyclopentanol hydrochloride (1.38 g) was heated to reflux in isopropanol (100 ml) containing DEA (3.87 g) for 18 hours. The cooling allowed the deposition of a powder which was separated by filtration, washed with propan-2-ol (50 ml) and dried under vacuum so as to collect the compound indicated in the title (2.35 g) , Mp 235-236 °.

15 c.c.m. (system B, 9: 1) Rf 0.23.

Example 3 N- (trans-5-hydroxycyclopent-2-enyl) adenosine

A mixture of 6-chlorpurine-ß-D-ribosine (0.86 g), trans-3-aminocyclopent-1-ene-4-ol 4-methylbenzene (0.69 g) and DEA was heated (0.52 g) in isopropanol (35 ml) at reflux, with stirring overnight and under a nitrogen atmosphere. The cooled mixture was concentrated in vacuo to collect an oil (2.56 g) which was purified by column chromatography on silica (Merck 9385, deactivated with 1% triethylamine), carrying out the elution with system B (10: 1), so as to obtain a solid (0.522 g). This solid was recrystallized from ethyl acetate (15 ml), so as to obtain the title compound (185 mg).

c.c.m. on silica deactivated with 1% triethylamine * 22 (system B, 10: 1) Rf 0.25.

1 H NMR δ 2.12-2.28 (1H, m), 2.65-2.80 (1H, m), 3.5- 3.78 (2H, m), 4.0 (1H, ddd) , 4.18 (1H, m), 4.35 (1H, m), 4.63 (1H, q), 5.05 (1H, lrra), 5.2-5.3 and 5.4-5 , 55 (4H, 5 2xm), .5.7 and 5.86 (2H, 2xm), 5.92 (1H, d), 7.92 (1H, lrd), 8.25 (1H, 1rs), 8.4 (IG, s).

Example 4 N- (cis-2-Hydroxycyclopent-4-enyl) adenosine, (diastereoisomers 1 and 2) A mixture of 6-chloropurine-8-D-riboside (2.01 g) was heated. -2-hydroxycyclopent-4-enylamine (1.42 g), DEA (2.71 g) and isopropanol (100 ml) at reflux for 20 hours. The solution thus obtained was adsorbed on silica and purified by column chromatography, eluting with system A (30: 8: 1), so as to collect a foam which is a triturated with system B (10: 1; 20 ml) so as to obtain crystals (1.05 g).

The mother liquors were evaporated to dryness and the solid thus obtained was recrystallized from methanol (5 ml), so as to obtain the diastereoisomer 1 of the title compound (0.31 g).

200

Rotary power C = 0.5465% (w / v) in DMSO / q7 D = 1.5 °.

Analysis found: C, 50.5; H, 5.5; N, 19.5; C15H19N5 * 0.4CH40 * 0 * 1H20 exi9e Cf50.8; H, 5.8; N, 19.2%.

The crystals (1.05 g) were recrystallized from methanol (20 ml) so as to obtain the diastereoisomer 2 of the title compound (0.46 g), mp 212.5-214 °.

20 °

Rotatory power C = 0.52957% (w / v) in DMSO ftJ ^ = 131.8 °.

Analysis found: 0.50.9, H, 5.5; N, 19.9; i 23 C15H19N5 ° 5 '°' 2H20 requires c * 51 ”05; 5.5; N, 19.8%.

Example 5 N- (cis-2-Hydroxycyclopent-4-enyl) adenosine

A mixture of 6-chloropurine-ß-D-5 riboside (2.01 g), cis-2-hydroxycyclopent-4-enylamine hydrochloride (1.42 g), DEA (3.19 g) was heated and isopropanol (100 ml) at reflux for 22 hours. The solution thus obtained was adsorbed on silica and it was purified by column chromatography, eluting with system B (5: 1) so as to collect the compound indicated in the title (1.7 g), in the form of a foam, ccm (system A, 50: 8: 1) Rf 0.11.

Analysis found: C, 49.5; H, 5.6; N, 18.9; C15H19N5 ° 5 * ° '9H2 ° requires C, 49.3; H, 5.7; N, 19.2%.

Example 6 N- (trans-2-Hydroxycyclopentyl) -2-methyladenosine

A mixture of 6-chloro-2-methyl-9- (8-D-ribofuranosyl) -9H-purine (902 mg), trans-2-aminocyclopentanol (404 mg), DEA (517 mg) was heated and 20 isopropanol (35 ml) at reflux with stirring for 22 hours under a nitrogen atmosphere. Additional trans-2-aminocyclopentanol (202 mg) and DEA (259 mg) were added and heating was continued at reflux for an additional 5 hours. The cooled mixture was concentrated in vacuo and the residual foam (1.9 g) was purified by column chromatography on silica (Merck 9385, deactivated with triethylamine) eluting with system B (10 : 1), so as to obtain a solid (1.01 g). This product was repurified by column chromatography on silica (Merck 9385) at 9 24 (eluting with system B (10: 1), so as to obtain the compound indicated in the title (0.57 g ), Mp 188-192 °.

Analysis found: C, 52.6; H, 6.5; N, 19.0; 5 C16H23N5 ^ 5 ex ^ 9th C, 52.6; H, 6.3; N, 19.2%.

Example 7 N- (23-Hydroxy-2-methylcyclopentyl) adenosine

A mixture of 6-chloropurine-ß-D-riboside (1.0 g) and trans-2-amino-1-10 methylcyclopentanol hydrochloride (0.55 g) was heated in isopropanol (50 ml) containing DEA (1.35 g) at reflux for 24 hours. The solution was adsorbed on silica and purified by column chromatography eluting with system B (9: 1) to collect a powder. Crystallization from isopropyl acetate and methanol gave the title compound (0.75 g), c.c.m. (system B, 9.1) Rf 0.35.

Analysis found: C, 50.9; H, 6.6; N, 18.0; 20 C16H23N5 ° 5 * 0.1C5H10 ° 20.75 H2 ° exi9e Cf51 "1; H, 6.5; N, 18.05%.

Example 8 N- (cis-3-Hydroxycyclopentyl) adenosine

6-chloropurine-ß-D-riboside (1.0 g), cis-3-aminocyclopentanol (0.48 g) and DEA (0.96 g) were stirred at reflux in isopropanol ( 50 ml), for 30 hours. The husky solution was allowed to cool to room temperature and concentrated in vacuo. Purification by CIC by eluting with System A (50: 10: 1) provided the title compound (0.9 g) as a foam.

c.c.m. (system A, 50: 10: 1) Rf 0.4.

Analysis found: C, 50.3; H, 6.3; N, 18.9; C15H21N5 ° 5 · 0 »5H20 · 0'2C4H8 ° 2 exi9e C, 50, l; H, 6.2%.

5 N, 19.0%.

Example 9 N- (trans-4-Hydroxycyclohexyl) adenosine

A mixture of 6-chloropurine-6-D-riboside (1.15 g), trans-4-aminocyclohexanol hydrochloride (0.61 g), triethylamine (1.12 ml) and isopropanol (50 was heated ml) at reflux for 18 hours. Additional trans-4-aminocyclohexanol hydrochloride (0.30 g) and triethylamine (0.56 ml) were added and heating continued for 7 hours. Additional trans-4-aminocyclohexanol hydrochloride (0.30 g) was added as well as triethylamine (0.56 ml) and heating continued for an additional 18 hours. The mixture thus obtained was adsorbed on silica and purified by column chromatography, eluting with system A (30: 8: 1), so as to collect a foam. This foam was washed in hot ether which was then evaporated so as to leave the title compound (0.82 25 g) in the form of a solid.

c.c.m. (system A, 30: 8: 1) Rf 0.41.

Analysis found: C, 52.2; H, 6.5; N, 18.7; C16H23N5 ° 4 ex ^ 9e: C, 52.6; H, 6.3; N, 19.0% /

Example 10 30 N- (trans-2-Hydroxycyclohexyl) adenosine

A mixture of 6-chloropurine-3-D-26 riboside (1.15 g), trans-2-hydroxycyclohexylamine hydrochloride (0.67 g), DEA (1.14 g) and isopropanol (50 ml), at reflux, for 22 hours. The solution thus obtained was adsorbed on silica and purified by column chromatography, eluting with system A (30: 8: 1), so as to collect a foam which is dissolved in ethanol (50 ml) and again adsorbed on silica. Further purification by column chromatography eluting with system B (5: 1) gave a solid which was dissolved in ethyl acetate (20 ml) and precipitated with cyclohexane (80 ml), so as to obtain the compound indicated in the title (0.48 g).

15 c.c.m. (system B, 10: 1) Rf 0.10.

Analysis found: C, 53, 1, H, 6.7; N, 17.9; C16H23N5 ° 5.0'2C6H12 * 0.22H2O exi9e C, 53.5; H, 6.7; N, 18.15%.

Example 11 20 N- (cis-2-Hydroxycyclohexyl) adenosine

A mixture of 6-chloropurine-8-D-riboside (1.15 g), cis-2-hydroxycyclohexylamine hydrochloride (0.67 g), DEA (1.14 g) and isopropanol was heated 50 ml), at reflux, for 30 hours. The solution thus obtained was adsorbed on silica and purified by column chromatography, eluting with system B (2: 1), so as to obtain a solid which was dissolved in l ethanol (100 ml) and again adsorbed on silica. Further purification by column chromatography eluting with system B (5: 1) gave a solid which was recrystallized from methanol (20 ml) to collect the title compound (0 , 32 27 g), mp 210-211 °.

c.c.m. (system B, 5: 1) Rf = 0.27.

Example 12 N- (trans-3-Hydroxycylohexyl) adenos ine 5 A mixture of 6-chloropurine-ß-D-riboside (1.0 g) and trans-aminocyclohexanol hydrochloride (0.53 g) was heated Isopropanol (50 ml) containing DEA (1.35 g), at reflux, for 3 days. The suspension thus obtained was adsorbed on silica and purified by column chromatography, eluting with system A (30: 8: 1), so as to collect a foam.

Crystallization from a mixture of isopropanol and ethyl acetate gave the title compound (0.7 g).

c.c.m. (system A, 50: 8: 1) Rf 0.27. analysis found: C, 51.8; H, 6.6; N, 18.2; C ,, H_qNcOc.0,1 CcHin0o.0,5H_0 requires C, 51.5; H, 6.55; lO Z j DD D lu 2 2 N, 18.2%.

Example 13 N- (cis-3-Hydroxycyclohexyl) adenosine

6-chlorpurine-ß-D-riboside (1.0 g) and cis-3-aminocyclohexanol hydrochloride (50.53 g) were treated according to the method described in Example 12 (except that 1 the mixture was heated at reflux for 2 hours), so as to collect the compound indicated in the title (0.58 g), ccm (system A, 30: 8: 1) Rf 0.27.

Analysis found: C, 52, 1; H, 6.9; N, 17.2; C16H23N5O5‘0.3C5H10O2‘0'5H2O exi9e C, 51.9; H, 6.7; N, 17.3%.

28

Example. 14 N- (trans-4-Hydroxycyclohexyl) -2-methyladenosine

A mixture of 6-chloro-2-methyl-9- (ß-D-ribofuranosyl) -9H-purine (902 mg), trans-4-aminocyclohexanol hydrochloride (1.14 g) and DEA were heated (1.94 g) in isopropanol (50 ml) at reflux, with stirring and under nitrogen for 17 hours. The cooled reaction mixture thus obtained was adsorbed on silica (Merck 9385) and purified by column chromatography on silica (Merck 9385) not eluting with system B (10: 1 , then 8: 1), so as to obtain the compound indicated in the title (0.9 g) in the form of a solid, ccm (system B, 5: 1) Rf 0.2.

Analysis found: C, 52.3; H, 6.7; N, 16.7; C17H25N5 ° 5'0'33C4H8O2 * 0.67 requires C, 52.3; H, 6.95; N, 16.6%.

Example 15 N- (cis-2-Hydroxycyclopentyl) adenosine A mixture of N- (cis-2-hydroxycylopent-4-enyl) adenosine (1.6 g), 5% platinum was stirred on charcoal (0.3 g) and ethanol (80 ml) in the presence of hydrogen for 20 hours. The mixture thus obtained was filtered and the filtrate was evaporated. The residue was dissolved in methanol (50 ml) and the solution was evaporated to give the title compound (1.2 g) as a foam, c.c.m. (system A, 30: 8: 1) Rf 0.30.

Analysis found: C, 49.6; H, 6.15; N, 19.1; C15H2] N505.0.3CH40.0.5H20 requires C, 49.6; H, 6.3; N, 18.9%.

29

Example 16 N- (trans-2-Hydroxycyclopentyl) adenosine

A mixture of 6-chloropurine-3-D-riboside (1.15 g), trans-2-aminocyclopentanol (0.41 5 g), triethylamine (0.41 g) and isopropanol (50 was heated ml), at reflux, for 20 hours. Additional amounts of trans-2-aminocyclopentanol (0.08 g) and triethylamine (0.08 g) were added and heating continued for 4 hours. The mixture 10 thus obtained was adsorbed on silica and purified by column chromatography, eluting with system A (30: 8: 1), so as to obtain a solid (0.48 g). This was repurified by column chromatography, eluting with the B 15 system (12: 1), so as to collect a foam which was triturated with ether so as to obtain the compound. indicated in the title (0.31 g), in the form of a 2: 1 mixture of diastereoisomers. c.c.m. (system B, 12: 1) Rf 0.35.

Analysis found C, 50.8; H, 6.25; N, 18.8; C15H21N5 ° 5 * °, 17 (C2H5) 2 ° · 0 »5H2O requires C, 50.5; H, 6.4; N, 18.8%.

Example 17 N- (trans-3-Hydroxycyclopentyl) adenosine 25 6-chloropurine-ß-D-riboside (0.63 g) was stirred,

trans-3-aminocyclopentanol hydrochloride (0.3 g) and DEA (0.63 g), at reflux, in isopropanol (30 ml) for 3.5 days. The reaction mixture was allowed to cool to room temperature, so that a precipitate formed which was dissolved by the addition of methanol. The solution was adsorbed on silica (Merck 9385) and purified by CIC

* »I 30 eluting with system B (3: 1) so as to obtain a powder. Final purification by column chromatography on silica (Merck 7734), eluting with system B (3: 1) gave the compound indicated in the title (44 mg), mp 208-210 ° as '' a 52:48 mixture of diastereoisomers.

RMNΧΗ δ 1.4-2.2 (6H, m), 3.5-3.79 (2H, m), 3.99 (1H, m), 4.1-4.2 (1H, m) , 4.2-4.3 (1H, m), 4.55 (1H, d), 4.62 (1H, m), 4.8 (1H, lrm), 5.22 (1H, d), 5.42-5.52 (2H, m), 5.9 10 (1H, d), 7.82 (1H, lrd), 8.2 (1H, lrs), 8.83 (1H, s).

Example 18 N- (cis-4-Hydroxycyclohexyl) adenosine

6-chloropurine - $ - D-riboside (1.0 g), cis-4-aminocyclohexanol hydrochloride (0.53 g) and DEA (0.96 g) were stirred at reflux in 1 'isopropanol (50 ml) for 20 hours. After cooling to room temperature, the solution was adsorbed on Florisil and purified by column chromatography, eluting with system A 20 (50: 8: 1) so as to obtain a foam. Further purification by column chromatography, performed as previously described, gave the title compound as a foam (0.55 g) 25 c.c.m. (system A, 50: 8: 1) Rf 0.07.

Analysis found: C, 51.9; H, 7.0; N, 17.5; C16H23N5O5 * 0'55EtOH'O, 3H2 ° requires C, 51.85; H, 6.8; N, 17.7%.

Example 19 30 / Ία, 23.3 3.7-N- / 2-Hydroxy-3-methylcyclohexyl7 adenosine

A mixture of 6-chloropurine-ß-D-31 * riboside (1.0 g), £ 1c hydrochloride, 2a, 6ß_7-6-amino-2-methylcyclohexanol (0.58 g) and DEA was heated. (0.9 g) in isopropanol (35 ml) at reflux for 26 hours. The solution thus obtained was adsorbed on Florisil and purified by column chromatography, eluting with system B (20: 1), then (10: 1) so as to collect the indicated compound. in the title (0.884 g), mp 128-133 °, in the form of a 47:53 mixture of diastereoisomers.

10 c.c.m. (system B, 5: 1) Rf 0.65.

Analysis found: C, 53.0; H, 6.8; N, 16.8; <'17H24N505 * 0, ^ (' 4H8 ^ 2 * ®'5H20 requires C, 52.8; H, 6.7; N, 16.9%.

Example 20 2-Chloro-N- / T.S, trans) -2-hydroxycyclopenty3 Jadenosine

A mixture of 2,6-dichloro-9- (2 ', 3', 5'-tri-O-benzoyl-ß-D-ribofuranosyl) -9H-purine (1.68 g) was stirred. (1S, trans) -2-aminocyclopentanol (380 mg) and DEA (1.4 ml) in isopropanol (2.25 ml) and heated at reflux for 5.5 hours under a d atmosphere 'nitrogen. The mixture was concentrated in vacuo and the solution of the residue in methanol (25 ml) was treated with an aqueous solution of ammonia (2 ml). The resulting mixture was stirred for 16 hours and then concentrated in vacuo. The residue was purified by column chromatography, eluting with system A (75: 8: 1), so as to obtain a foam (570 mg). This foam was dissolved in ethyl acetate (10 ml) and the solution thus obtained was poured into cyclohexane (80 ml), so as to collect a solid. The solid and the crystallization liquor were combined. The whole was concentrated in vacuo and the residue was dissolved in methanolic ammonia "1" 32 (10 ml). The solution was allowed to stand for 4 hours and was then concentrated in vacuo to give an oil (570 mg) which was purified by column chromatography, eluting with system A ( 50: 8: 1), so as to collect the title compound (212 mg). c.c.m. (system A, 50: 8: 1) Rf 0.16.

Analysis found: C, 45.9; H, 5.55; N, 16.7; C15H20C1N3O5.0'5C2H6O * O, 6H2O exi9e C, 45.85; H, 5.7; 10 N, 16.7%.

Example 21 2-Chloro-N-) Γ (IR, trans) -2-hydroxycyclopenty] jAadenosine

A mixture of 2,6-dichloro-9- (2 ', 3', 5'-tri-O-benzoyl-3-D-ribofuranosyl) -9H-purine (1.68 g) was stirred, hydrochloride (IR, trans) -2-aminocyclopentanol (380 mg) and DEA (1.4 ml) in isopropanol (25 ml) and heated at reflux for 5 hours under nitrogen. The reaction mixture was concentrated in vacuo and the solution of the residue was treated in inethanol 20 (10 ml) with methanolic solution saturated with ammonia (20 ml) and kept at room temperature for 8 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with system A 25 (50: 8: 1), so as to obtain a glass (770 mg). This was dissolved in hot ethyl acetate (40 ml) and the solution thus obtained was poured into cyclohexane (160 ml), so as to collect a solid (447 mg). This solid was combined with the residue from evaporation of the crystallization liquor and the solid thus obtained (1.2 g) was adsorbed on silica and it was purified by column chromatography while carrying out the elution with system A (75: 8: 1), then Μ 33 (50: 8: 1), so as to obtain a glass (830 mg). This glass was dissolved in hot ethyl acetate (20 ml) and the solution thus obtained was poured into cyclohexane (160 ml) so as to collect the title compound 5 (598 mg) in the form of a solid, ccm (system A, 50: 8: 1) Rf 0.20.

Analysis found: C, 47.6; H, 5.5; N, 17.35; C15H20ClN5O5 * ° '1C6H12 exi9e c.47,55; H, 5.4; N, 17.75%.

Example 22 10 trans-2-Chloro-N- (4-hydroxycyclohexyl) adenosine

A mixture of 2,6-dichloro ~ 9- (21.3 ', 5'-tri-0-benzoyl- (3-D-ribofuranosyl) -9H-purine (1.68 mg), of hydrochloride was stirred. trans-4-aminocyclohexanol (424 mg) and DEA (1.4 ml) in isopropanol (25 ml) and heated under reflux under nitrogen for 4.5 hours. reaction mixture for 30 minutes and concentrated in vacuo to collect a foam which was dissolved in methanol (10 ml) and a methanolic solution saturated with ammonia (20 ml) was added. kept the solution thus obtained at room temperature for 6 days and was then adsorbed on silica and purified by column chromatography, eluting with system A (75: 8: 1, then 25 30 : 8: 1), so as to collect an oil which crystallized on standing to give a solid (1.02 g), which was dissolved in ethanol, filtered and concentrated. vacuum filtrate and triturated with ethyl acetate e so as to obtain a solid. The solid was repurified by column chromatography, eluting with system B (5: 1), so as to collect the title compound (405 mg), mp 203-204 °.

4 * 34

Analysis found: C, 47.9; H, 5.6; 14.15.75; C16H22C1N505 * 0'35C4H802‘0,4H20 requires C, 47.75; H, 5.9; N, 16.0%.

Example 23 5 N- £ t lS, trans) -2-Hydroxycyclopentyl7adenosine, salt with fumaric acid (1: 1)

Fumaric acid (1.2 g) was added to a reflux solution of N- / T (1S, trans) -2-hydroxycyclopentyl_7adenosine (7.03 g) in isopropanol (105 ml). The hot solution thus obtained was filtered and the filtrate was cooled and the filtrate was allowed to crystallize. After 2 hours at 20 °, the crystalline product was isolated by filtration, washed with isopropanol (10 ml) and dried in vacuo at 50 ° for 20 hours so as to collect the compound indicated in the title (6.5 g), having a melting point of 179-180 °. The chromatographic behavior of this salt resembled that of an authentic sample of the free base.

Example 24 N- £ 1S, trans) -2-Hydroxycyclopentyl7adenosine, acid salt (lS) - (+) - 10-camphosulforic

A mixture of N- £ i (1S, trans) -2-hydroxycyclopentyljadenosine (3.51 g) and (lS) - (+) - camphosulfonic acid (2.44 g) was heated in isopropanol (35 ml) at reflux, under a nitrogen atmosphere, until a clear solution is obtained. The solution was diluted with ethyl acetate (50 ml) and the mixture was cooled to about 25 ° with stirring. The crystalline solid thus obtained was isolated by filtration, washed with a mixture of isopropanol and ethyl acetate (1: 2; 2 x 15 ml) and dried in vacuo at 40 ° so as to collect the compound indicated in the title (5.31 g, PF 150-152 °.

Analysis found: C, 51.25; H, 6.7; N, 11.9; S, 5.3; 5 C25H3N5 ° 9S requires C, 51.4; H, 6.4; N, 12.0; S, 5.5%.

Example 25 N- (trans-2-Hydroxycyclooctyl) adenosine

A mixture of trans-2-aminocyclooctanol (0.34 g), 6-chloropurine-ß-D-riboside (0.70 g) and DEA (0.60 g) was heated to reflux in 1 ' isopropanol (25 ml) for 24 hours. The solution thus obtained was adsorbed on Flurosil and purified by chromatography, eluting with system B (9: 1), so as to collect the title compound (0.43 g ), ccm (system B, 9: 1) Rf 0.38.

Analysis found: C, 53.05; N, 7.0; N, 16.9; C18H27N505. 075H2O requires C, 53, 1; H, 7.1; N, 17.2%.

The following examples illustrate pharmaceutical compositions according to the present invention which contain N- £ (1S, trans) -2-hydroxycyclopentyl7adenosine as the active ingredient. Physiologically acceptable salts and / or physiologically acceptable solvates of this compound and other compounds of formula (I) can be similarly put into pharmaceutical compositions as also their physiologically acceptable solvates and / or salts.

♦ 36 1. Oral capsule per capsule

Active ingredient 50 mg

Magnesium stearate 0.5 mg 5 Starch 1500 * 49.5 mg * a form of directly compressible starch.

The sieved drug is mixed with the excipients. The mixture is introduced into hard gelatin capsules of appropriate size using a suitable filling machine.

2. Oral syrup per 5 ml dose

Active ingredient 25 mg

Hydroxypropylmethylcellulose, U.S. Pharmacopeia 15

(viscosity type 4000) 25 mg

Buffer )

Aroma)

Colorant) as required 20 Preservative)

Sweetener)

Purified water up to 5 ml

Disperse the hydroxypropyl methylcellulose in hot water, cool and then mix with an aqueous solution containing the active ingredient and the other components of the composition. Adjust the resulting solution to volume and mix. Clarify the syrup by filtration and introduce it into glass bottles with suitable closures resistant to children.

i,! 1 '37 3. Oral tablet

Per tablet

Active ingredient 100 mg

Croscarmellose sodium 30 mg 5 Magnesium stearate 3 mg

Microcrystalline cellulose up to a tablet core weight of 300 mg

Sieve all the ingredients and mix them mutually in a suitable mixer until homogeneous. Compress with appropriate punches in an automatic tablet making machine. The tablets can be coated with a thin coating of polymer applied by conventional film coating techniques. A pigment can be incorporated into the coating.

4. Sublingual tablet

Per tablet

Active ingredient 2 mg

Hydroxypropylmethylcellulose 5 mg 20 Magnesium stearate 1 mg

Mannitol up to -65 mg tablet core weight

Sieve the active ingredient and mix with mannitol and hydroxypropyl methylcellulose. Add appropriate volumes of purified water to granulate. After drying, sift the granules, mix with magnesium stearate and compress with suitable punches in an automatic tablet making machine.

38 5. Solution for inhalation

Per 2 ml dose

Active ingredient 22 mg

Sodium chloride qs 5 Sodium hydroxide solution up to pH 7.2 Phosphate buffer pH 7.2 0.2 ml

Water for injection up to 2 ml

Dissolve the active ingredient in water suitable for injection. Dissolve the sodium chloride therein and titrate the solution thus obtained up to a pH of 7.2 with a solution of sodium hydroxide; add the phosphate buffer solution. Bring the solution to volume with water suitable for injection and sterilize by membrane filtration. Introduce aseptically into containers suitable for nebulization inhalation.

Claims (16)

1. Compounds of the formula (I) RNH 5 · // \ N · -n I t h ΛΛ / (η X N N u '0 ψ hctV NJ 2. Compounds of formula (I) according to claim 1, characterized in that X represents a hydrogen atom or the methyl radical and their solvates and physiologically acceptable salts. 3. Compounds of formula (I) according to claim 2, characterized in that X represents a hydrogen atom and their solvates and physiologically acceptable salts. 4. Compounds of formula (I) according to any one of claims 1 to 3, characterized in that R represents a cycloalkyl or cycloalkenyl ring, containing 5 or 6 carbon atoms, substituted by a hydroxyl radical and optionally substituted by a C 1 -C 4 alkyl radical and their physiologically acceptable solvates and salts> * '· ψ 40. 5. Compounds of formula (I) according to claim 4, characterized in that R represents a cycloalkyl ring containing 5 or 6 carbon atoms, substituted by a hydroxyl radical and optionally substituted by a C 1 -C 4 alkyl radical on the same carbon atom as the hydroxyl radical and their physiologically acceptable solvates and salts. 6. Compounds of formula (I) according to claim 5, characterized in that R represents the 2-hydroxycyclopentyl, 4-hydroxy-cyclohexyl, 3-hydroxycyclohexyl or 2-hydroxy-2-butylcyclohexyl radical and their physiologically solvates and salts acceptable. 7. Compounds of formula (I) according to claim 3, characterized in that R represents a cyclopentyl ring substituted by a hydroxyl radical and optionally substituted by a C 1 -C 6 alkyl radical and their physiologically acceptable solvates and salts. 8. N- ^ IS, Trans) -2-hydroxycyclopentyi7adenosine and its physiologically acceptable solvates and salts. 9. N - / "(1S, Trans) -2-hydroxycyclopentyl7adenosine; N- £ LR, trans) -2-hydroxycyclopentyJjadosine, their mixtures and their physiologically acceptable solvates and salts. 10. N- (Trans-4-hydroxycyclohexyl) -2-methyladenosine; N- (cis-4-hydroxycyclohexyl) adenos ine; N- (cis-2-hydroxycyclopentyl) adenosine; N- (trans-3-hydroxycyclohexyl) adenosine; N- (2 8-hydroxy-2-methylcyclopentyl) adenosine; N- (cis-2-hydroxycyclohexyl) adenosine; and their physiologically acceptable solvates and salts. 10 I | • _ <ÔH ÔH in which X represents a hydrogen atom or a chlorine atom, or the methyl radical and R represents a cycloalkyl or cycloalkenyl nucleus, containing from 5 to 8 carbon atoms, which nucleus is substituted by a radical hydroxyl and is optionally substituted by a C 1 -C 4 alkyl radical, as well as the solvates and salts of these compounds. 11. Compounds of formula (I) according to any one of claims 1 to 10 and their solvates and physiologically acceptable salts, to be used for the treatment of human or animal subjects suffering from a condition which it is advantageous to decrease the concentration of free fatty acids in the plasma and / or to reduce the conduction and the heart rate. 12. Use of a compound of formula (I) according to any one of claims 1 to 10, or of a solvate or a physiologically acceptable salt of such a compound, for the manufacture of a medicament intended to the treatment of human or animal subjects suffering from a condition in which it is advantageous to decrease the concentration of free fatty acids in the plasma and / or to reduce the conduction and the heart rate. 13. A method of treating human or animal subjects suffering from a state in which it is advantageous to decrease the concentration of free fatty acids in the plasma and / or to reduce the conduction and the heart rate, characterized in that an effective proportion of a compound of formula (I) according to any one of claims 1 to 10, or of a solvate or physiologically acceptable salt thereof is administered to the subjects. 14. Pharmaceutical composition, characterized in that it comprises, as active ingredient, at least one compound of formula (I) according to any one of claims 1 to 10, or a physiologically acceptable solvate or salt d 'such a compound, in combination with a pharmaceutical vehicle and / or excipient. 15. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that (a) a compound of formula (II) is reacted:. Λ * j 42 ι ιΓιί A Λ ί / ττ \ XNN (II) a Ο I 'm \ * Μ I_I' S μ OH ÖH in which L represents a labile radical and X has the meanings which were assigned to it in the claim 1, or a protected derivative of such a compound, on a compound of the formula RN ^ in which 5 R has the meanings which were allotted to him in claim 1, or a salt or protected derivative of such a compound, in basic conditions, this reaction being followed, if necessary, by the removal of any protective radicals; (B) when it is desirable to prepare a compound of formula (I) in which X represents a hydrogen atom or a methyl radical, a compound of formula (III) is subjected: NH \ A / V " "Λ / '! I_! OH OH £ ί 43 in which R has the meanings which have been assigned to it in claim 1 and X represents a hydrogen atom or the methyl radical, or a protected derivative of this compound, at a transposition reaction, 5 at temperature high and in the presence of a base, this reaction being followed, if necessary, by the removal of any protective radicals; (c) converting a compound of formula (I) into another compound of formula (I) by a method known per se; or (d) removing any protective radicals from a protected derivative of the compound of formula (I); any of the above processes being followed, if desired, by the conversion of a compound of formula (I) initially obtained to a salt thereof, or the conversion of a salt of the compound of formula (I) into a compound of formula (I), or another salt thereof; and any of the above methods being followed, if desired, by resolution of a racemate to obtain the desired enantiomorph. 16. The method of claim 15 (b) characterized in that the compound of formula (III) or a protected derivative thereof is prepared by the reaction of a compound of formula (IV) t | ! H2 // \ N.-N (IV) AA / XNN * 0 f / \ / M HO. * II • - · OH ÖH 44 in which X has the meanings which have been assigned to it in claim 14 (b), or a protected derivative thereof, on a strong basis, this reaction being followed by the reaction on a alkylating agent capable of introducing the desired radical R. *